Peripheral vascular smooth muscle (VSM) tone is regulated by intrinsic (VSM membrane and intracellular), endothelial and neural mechanisms. The overall objective of this proposed study is to further clarify mechanisms by which volatile anesthetics; e.g., isoflurane modulates the activity of the VSM intrinsic membrane and intracellular components and extrinsic endothelial factors that regulate VSM contractile force (tone) in hypertensive and normotensive animals. Specific aims of this proposal are to determine how isoflurane modulates intrinsic and endothelial control of VSM tone and examine the differential effects of isoflurane on mechanisms of VSM control in hypertensive vs normotensive animals. Studies will be conducted in situ in externalized, locally denervated small mesenteric resistance-regulating arteries and capacitance-regulating veins and in vitro by perfusing small mesenteric artery segments from spontaneously and salt-sensitive hypertensive rats. Active changes in VSM transmembrane potential (Em) and vessel diameter will be measured in situ in ketamine-pentobarbital anesthetized rats before and during inhalation of 1.0 MAC isoflurane and in vitro before and during superfusion with isoflurane. In separate in situ preparations, the effects of local block of: 1) each of the four specific K+ channels, 2) cGMP kinase, 3) endothelial nitric oxide and prostanoid synthesis will be determined with and without isoflurane. Intracellular Ca2+ activity and cGMP will also be assayed from vessel preparations with and without isoflurane. K+ channel and Ca2+ channel responses to the anesthetic will also be studied using the voltage patch and whole cell clamp techniques, respectively.